Methods of combatting gastropods with nitro substituted salicylanilides



United States Patent '0 No Drawing. Continuation-impart of application Ser. No.

462,127, June 7, 1965. This application Mar. 22, 1966, Ser. No. 536,257

7 Claims. (Cl. 16731) ABSTRACT OF THE DISCLOSURE Gastropodicidal methods employing 2-chloro-4'-nitrosalicylanilides characterized by having a branched chain alkyl grouping in the 3-position of the salicyl nucleus.

(CH2) H E wherein n is an integer from to 1, wherein A is halogen of atomic weight in the range of 35 to 80 (that is chloro or bromo, but preferably chloro), wherein E is ,chloro or,

and preferably hydrogen, and wherein R is alkyl containing from 3 to 8 carbon atoms specifically isopropyl or C tert.alkyl of the formula:

wherein R and R respectively are straight chain (or linear) alkyl and respectively satisfy the empirical formula C H wherein m is a whole number from 1 to 3, inclusive, and wherein x 'is an integer from 0 to 4, but preferably 0. It is preferred that R be C tertalkyl such as tert.butyl, tertpentyl, 1,1-dimethyl-n-butyl and l-ethyll-methyl-n-propyl. As illustrative of other variants of R are 1,1 dimethyl-n-pentyl, 1,1 dimethyl-n-hexyl, 1,1 di methyl-isoamyl, 1,1,3,3 tetramethyl-n-butyl, "1 ethyl 1- methyl-n-butyl and 1,1-diethyl-n-butyl.

The compounds of this invention are prepared by reacting substantially one mole of a 2-chloro-4-nitroaniline of the formula:

Patented Mar. 26, 1968 wherein E has the afore-described significance with substantially one mole of a substituted S-halosalicylicv acid of the formula:

wherein n, A and R have the afore-described significance in the presence of from about 0.33 to about"1.0 mole of phosphorus trichloride and an inert organic liquid (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene, and the like, and mixtures thereof) at a temperature above the freezing point of the reaction system up to and including the systems boiling point, however, in general the reaction'temperature will be in the range of from about 60 C. to about 200 C. The substituted 2-chloro-4-nitrosalicylanilide end products are solids and are insoluble in water.

As illustrative of the 5-halosalicylic acid precursors are 3-isopropyl-5-chlorosalicylic acid (M.P. 169-170 C.), 3- tert.bu tyl-S-chlorosalicylic acid (M.P. 220-222 C.), 6- methyl-3-tert.butyl-S-chlorosalicylic acid (M.P. 208211 C.), 3-tert.pentyl-S-chlorosalicylic acid (M.P. 195-198" C.), 6-methyl-3-tert.butyl-5-brornosalicylic acid (M.P. 170173 C. 3-(1,l-dimethyLn-butyl)-5-chlorosalicylic acid (M.P. 154.5 155 C.), 3-(l-ethyl-l-methyl-n-propy1)-5-chlorosalicylic acid (M.P. 15-2154 C.), 6-methyl- 3-(1,1-dimethyl n butyl) 5 chlorosalicylic acid (M .P. 154.5l56 C.), 3-tert.butyl-S-bromosalicylic acid (M.P. 230-231.5 C.), and 3-( 1,1,3,3-tetramethyl-n-butyl)-5- chlorosalicylic acid (M.P 147 C.). The salicylic acid precursors for these S-halosalicylic acids are either known materials or readily prepared by initially orthoalkylating phenol or m-cresol with the appropriate olefin in accordance with the procedure of-Stroh et al., Angew. Chem. vol. 69, pp. 699-706 (1957) to provide the substituted phenol wherein R and n have the afore-described significance (many of these substituted phenols are commercially available) and then carboxylating with carbon dioxide in the presence of aqueous sodium hydroxide in accordance with the Schmitt modification of the Kolbe synthesis (German Patents 29,939 and 38,742) and thereafter acidifyingthesodium salt so produced. These salicylic acids are readily halogenated in the 5-position thereof employing chlorine or bromine in the presence of glacial acetic acid.

As illustrative of the compounds of this invention and their preparation but not limitative thereof is the following:

Example I trichloride in 55 parts by weight of chlorobenzene. The reaction mass is then refluxed (about 135 C.) for five hours. The mass is then cooled to about 70 C. whereupon and with agitation is added 50 parts by weight of water followed by 50 parts by weight of percent hydrochloric acid. The organic layer is separated and washed first with water then with dilute aqueous sodium bicarbonate and finally with water. The so washed organic mass is then stripped of volatiles under vacuum. The residue upon recrystallization from benzene gave 3-isopropyl-2',5-dichloro-4'-nitrosalicylanilide, M.P. 12012l C.

Other illustrative examples of the compounds of this invention (Examples II to XIII below) prepared by the same procedure as in Example I but substituting the appropriate substituted salicylic acid and appropriate substituted aniline in the same molecular proportions are summarized in tabular form below:

Example No.:

II 3-tert.butyl-2,S-dichloro-4'-nitrosalicylanilide (M.P. 159l60 C.).

ro-4-nitrosalicylanilide (M.P. 146-148 C.

The salicylanilides of this invention are useful in combatting gastropods, such as the aquatic and amphibious snails, which are a class of animal life Gastropoda within the phylum Mollusca, which cause considerable agricultural and horiticultural damage, and the snails and slugs of this class of animal life which are the necessary intermediate host or vector in the life cycle of various common parasites, as for example the trematodes or fiukes which are parasitic in man and animals causing schistomiasis and like diseases.

As illustrative of the gastropodicidal properties of the salicylanilides of this invention but not limitative thereof as compared to analogues thereof is the following:

Three snails (Planobarius corneus, the species of snail host of the cyclo'coelid T racheophilus sisousi, the blood fluke Bilharziella polonica and other trematodes) of 6 to 8 Weeks of age are placed in a 200 x 32 mm. tube (three replicates) and thereto is added the salicylanilide to be 1 evaluated in the form of an aqueous dispersion thereof having a concentration in parts per million, that is p.p.m., thereof as set forth below. (This dispersion is prepared by dissolving sufficient of the salicylanilide in 10 ml. of acetone to make a one percent by weight solution thereof and thereafter adding sufficient water to give the desired concentration.) The percent kill (i.e., the average of the three replicates of three snails of each salicylanilide) at the end of 24 hours at room temperature for each of the below itemized salicylanilides at the itemized concentration in parts per million was found to be as follows:

Percent Kill at 2. Gone. in p.p.m. Salicylanilide 2,5-diehloro-4-nitrosalicylanilide 60 0 3-iS0pr0pyl-2 adichloro-4-nitrosalicylanilide. 100 100 30 3-tert.butyl-2 ,5-dichloro-4-nitrosalicylanilide 100 100 6-methyl3-tert.butyl-2,5-dichloro-4- nitrosalicylanilide 100 100 100 3-tert.pentyl-2 ,5-dichloro-4-nitrosalicylani1ide 100 100 3-tert.butyl-2,5-dichloro-5-nitrosalicylanilide. 100 10 0 8-tert.butyl-4,5-dinitro-2-chlorosalicylani1ide* 100 0 3-n-hexyl-2,5-dichloro-4-nltrosalicylanilide. 50 0 2,3,5-trichloro-4'-nitrosalieylanilide 100 0 3-tert.butyl-4,5-dichl0ro-2-nitrosalicylani1ide 30 0 3- (tn'fluoromethyl) -4-nitro-5-chlorosalieylanilide 100 0 3-tert.butyI-3-(trifluoromethyl) -4-nitro-5- chlorosalieylanilide 100 10 0 3-tert.butyl-4 fi-dichlorosalicylanilid 0 0 3,3,4,fi-tetrachlorosalicylanilide 100 0 Prepared by nitrating with a HNO3-H2SO4 mixture 3tert.butyl- 2-chloro-4-nitrosalicylanilide (M.P. 168-169 0.), the latter being prepared as aforedescribed by reacting 2-chloro'4 nitroaniline and 3-tert. butyl-sahcylie acid in the presence of phosphorus tricbloride.

In combatting the aquatic Gastropoda it is necessary to apply the gastropodicide to the waters or land areas adjacent thereto which form their habitats, and therefore to be practical the compounds of this invention must exhibit gastropodicidal activity at relatively high dilutions.

In combatting the amphibious Gastropoda the com pounds of this invention can be employed per se or formulated into a dust and dispersed or scattered on vegetation or on the ground along banks of streams, rivers, irrigation canals, or the edges of other bodies of water so that the amphibious Gastropoda will come in contact with the gastropodicidal agent when it leaves the water and begins to travel across ground areas.

Where the Gastropoda sought to be combatted has a water habitat the compounds of this invention can be added per se to the water, or in the form of a formulated dust cast on the surface of the water, or sprayed on the water in the form of a solution thereof or a liquid emulsion formulation thereof.

Inert diluent powders for the formulation of such dusts include fullers earth, diatomaceous earth, bentonite, talc, pyrophillite, soybean flour, wood flour, and walnut shell flour, which dusts preferably have a particle size of 5 microns or below and contain from 10 to 75 percent by weight of a compound of this invention. Ordinarily such dusts will be applied at the rate of about 25 to 50 pounds per acre of surface area. These dusts can also contain from 1 to 5 percent by weight of a non-ionic surfactant to provide a wettable dust formulation. Liquid formulations can be prepared by dissolving the compounds of this invention'in a suitable organic solvent such as acetone and sprayed as such or in admixture with a nonionic emulsifier to form a liquid emulsion formulation for spray purposes. The actual effective concentration of the compound of this invention for gastropodicidal purposes will depend upon the particular Gastropoda, weather conditions, and whether it is to be applied directly to the water which forms the habitat for the Gastropoda or to land areas which are crossed by amphibious Gastropoda either as the compound per se or in the form of formulations thereof. Those skilled in this art can readily determine the proper concentration for any particular application by knowing the particular dilution factor, which is generally expressed as the maximum aqueous dilution which will produce a 50% kill at a dilution of one part by weight per 8000 parts by weight of water.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of combatting gastropods which comprises subjecting the gastropods to a gastropodicidally toxic amount of a substituted 2'-ch1oro-4'-nitrosalicylanilide of the formula R OH Cl I A (oHnuH E wherein R and R" respectively are straight chain alkyl of the formula C H wherein m is a whole number from 1 to 3, and wherein x is an integer from zero to 4.

2. A method of claim 1 wherein A is chloro, wherein E is hydrogen, wherein R contains from 4 to 6 carbon atoms and is C tert.alkyl, and wherein x is zero.

3. A method of claim 1 wherein n is zero, wherein A is chloro, wherein E is hydrogen, and wherein R is tert.butyl.

4. A method of claim 1 wherein n is zero, wherein A is chloro, wherein E is hydrogen, and wherein R is tort-pentyl.

5. A method of claim 1 wherein n is one, wherein A is chloro, wherein E is hydrogen, and wherein R is tert.butyl.

6. A method of claim 1 wherein n is one, wherein A is chloro, wherein E is hydrogen, and wherein R is tert.pentyl.

7. A method of claim 1 wherein n is zero, wherein A is chloro, wherein E is hydrogen, and wherein R is isopropyl.

References Cited UNITED STATES PATENTS 3,079,297 2/1963 Schraufstatter 1673'1 ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner. 

